The mutational landscapes underlying aggressiveness in adenoid cystic carcinoma Adenoid cystic carcinoma (ACC) is an epithelial malignancy that commonly arises from major and minor salivary glands. This malignancy is associated with very significant morbidity and mortality. It is remarkable for its high rate of perineural invasion, a high tendency for recurrence, and ultimately, low rates of survival. Ten year survival rates are approximately 40%. ACC is an understudied malignancy for which the molecular alterations underlying tumoigenesis are obscure. Our long-term goal is to understand the genomic changes that lead to ACC and to use this information to develop better therapeutic and diagnostic modalities for ACC patients. The central hypothesis of this application is that important genetic alterations in ACC tumors underlie the clinical behavior of these tumors. Through a systematic approach employing global, large-scale analysis of primary tumors with diverse clinical outcomes, state-of-the art next generation sequencing and analysis, and validation of putative genetic alterations prognostic of recurrence, we propose to elucidate the mutational landscape underlying ACC aggressiveness. Our whole exome sequencing effort so far shows that the mutational profile of ACC is distinct from that of other cancers. The objective of this proposal is to understand the genetic alterations underlying ACC pathobiology. We plan to accomplish our objective by pursuing the following 2 specific aims. In Aim 1, we will elucidate the mutational landscapes of adenoid cystic carcinoma with varying tumor aggressiveness. Here, we will use next generation whole exome sequencing and our robust bioinformatics analysis pipeline that we have established, to elucidate the mutational landscape of a discovery set of ACC tumors. We will utilize a systems-based analysis to dissect the key biological pathways that are disrupted in ACC. Lastly, we will determine the genetic alterations that are prognostic of clinical outcome. In Aim 2, we will validate mutations that drive tumor aggressiveness in ACC. In this aim, we will validate the mutations and their frequencies discovered in our discovery cohort. Our hypothesis here is that there exist recurrent mutations in ACC that dictate tumor pathogenesis. To test this hypothesis, rigorous bioinformatic and statistical approaches will be used to identify the most common somatic alterations in ACC and those that affect recurrence and survival in our discovery set. We will use targeted sequencing of these genes to validate their frequencies of occurrence and the extent to which they determine aggressive pathobiology. We will utilize a large validation set (n=87) of ACCs which span the spectrum of tumor aggressiveness. Successful completion of this work will elucidate the genetic changes underlying ACC, uncover the mutations that drive tumor aggressiveness, and help identify potential novel targets for therapy.